Gout….Academic Detailing Service 4 Introduction This handout addresses issues regarding some...
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Gout…. Update 2013
Transcript of Gout….Academic Detailing Service 4 Introduction This handout addresses issues regarding some...
Gout….
Update 2013
Academic
Detailing
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Planning committee
Content Experts Clinical experts
Juris Lazovskis MD ABIM, Assistant Professor, Department of Medicine, Division of Rheumatology, Dalhousie University; Consultant Rheumatologist, Cape Breton Regional Hospital
Michael L West BSc MD FRCPC FACP, Professor, Department of Medicine, Dalhousie University
Drug evaluation pharmacist Heather McLearn BScPharm, Drug Evaluation Unit, Capital Health
Family Physician Advisory Panel Bernie Buffett MD, Neils Harbour, Nova Scotia
Ken Cameron BSc MD CCFP, Dartmouth, Nova Scotia
Norah Mogan MD CCFP, Liverpool, Nova Scotia
Dalhousie CME Michael Allen MD MSc – Family Physician, Director Evidence-based Programs and Academic
Detailing Service
Michael Fleming MD CCFP FCFP – Family Physician, Director Family Physician Programs in CME
Academic Detailers Isobel Fleming BScPharm ACPR, Senior Academic Detailer
Julia Green-Clements BScPharm
Gabrielle Richard-McGibney BScPharm, BCPS, PharmD
Cathy Ross RN BScNursing
Disclosure statements
The Academic Detailing Service is operated by Dalhousie Continuing Medical Education and funded by the Nova Scotia Department of Health and Wellness. Dalhousie University Office of Continuing Medical Education has full control over content.
Dr Michael Allen has received funding from the Nova Scotia Department of Health and Wellness for research projects and to develop CME programs.
Dr Juris Lazovskis has no disclosures.
Dr. Michael West has no disclosures pertinent to this document.
The cover image is courtesy of Wikipedia. It is titled “The Gout” by James Gillray. Published May 14, 1799
Cite this document as: Gout: Update 2013, Dalhousie CME Academic Detailing Service, November 2013, http://cme.medicine.dal.ca/ad_resources.htm Please direct correspondence to: Dr Michael Allen, [email protected] © Copyright 2013 Dalhousie Academic Detailing Service
The information contained in this document, and related presentations made by representatives of the Academic Detailing Service, are based on current literature and recommendations. Although care has been taken in preparing this material, Dalhousie University does not and cannot guarantee its accuracy. Physicians must use their own discretion in applying this information to individual patient care. Anyone using the information does so at their own risk and shall be deemed to indemnify Dalhousie University and individual representatives of the Academic Detailing Service from any and all injury or damage arising from such use.
“Seek simplicity, and mistrust it.”
Alfred North Whitehead
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Table of Contents
Tables and appendices ............................................................................................. 2
Definitions and abbreviations .................................................................................... 3
Introduction ............................................................................................................... 4
Question 1. What are the treatment options for acute gout? ...................................... 5
Question 2. How should urate lowering therapy (ULT) be started and monitored? .... 6
Question 3. What are some special considerations when treating gout? ................. 12
Question 4. What is the role of lifestyle in prevention of gout? ................................. 14
References .............................................................................................................. 15
Tables and Appendices
Table 1 Drugs and conditions associated with hyperuricemia and gout ..................... 5
Table 2 Summary of oral drug treatments for acute and prophylactic treatment of gout ......................................................................................... 17
Appendix 1 Table of select gout studies .................................................................. 19
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Definitions and Abbreviations
ACR
AE
American College of Rheumatology
Adverse event
AHS
CrCl
eGFR
MI
NICE
SUA
Allopurinol hypersensitivity syndrome
Creatinine clearance
Estimated glomerular filtration rate
Myocardial infarction
National Institute for Health and Care Excellence
Serum uric acid
ULT Urate lowering therapy
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Introduction
This handout addresses issues regarding some current recommendations for the management of gout and a review of the supporting evidence.
Gout is a condition that presents as a spectrum of clinical and pathologic features caused by an excess body burden of uric acid, manifested in part by hyperuricemia which is generally defined as a serum urate level greater than 400µmol/L.
Tissue deposition of monosodium urate monohydrate crystals in supersaturated extracellular fluids of the joint, and certain other sites, causes most of the clinical and pathologic features of gout.
In developing this topic we have reviewed
o American, British, and European guidelines
o Cochrane reviews
o Up To Date
o FDA reports
o Original publications
We will address four questions
1. What are the treatment options for acute gout?
2. How should urate lowering treatment (ULT) be started and monitored?
3. What are some special considerations in treating gout?
4. What is the role of lifestyle in prevention of gout?
Treatment recommendations are frequently supported by consensus or small studies rather than large high quality randomized controlled trials. For some recommendations that may have changed recently we have provided supporting evidence in Appendix 1.
People can have hyperuricemia without gout; asymptomatic hyperuricemia does not require treatment.
Several drugs and conditions are associated with hyperuricemia and gout (Table 1).
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Table 1 Drugs and conditions associated with hyperuricemia and gout¹
Drugs Conditions
Alcohol Excessive alcohol use
Cyclosporine Atherosclerosis
Cytotoxic chemotherapy Chronic kidney, glomerular, interstitial renal disease
Diuretics (thiazide and loop) Diabetes
Ethambutol Hyperlipidemia
Interferon + ribavarin Hypertension
Levodopa Ischemic heart disease
Nicotinic acid (niacin) Lead intoxication
Pyrazinamide Metabolic syndrome
Salicylates, low-dose Myeloproliferative disorders and some cancers
Tacrolimus Obesity, dietary factors
Teriparatide Urolithiasis history
Genetic or acquired causes of uric acid
overproduction (rare)
Reprinted with permission of Canadian Pharmacists Association, e-Therapeutics
Question 1. What are the treatment options for acute gout?
Treatment should begin as soon as possible after an acute episode starts, ideally within 24 hours.²
Non-pharmacological therapy includes topical ice packs.²
Various guidelines recommend the following drugs for treatment of acute episodes:
o Colchicine
Used to be given until onset of GI symptoms but fixed low dose (total 1.8 mg on the first day) is now recommended because it is as effective and less likely to cause adverse effects.³
Must be given within 36 hours of onset of attack.
o NSAIDS
Although indomethacin has been commonly used, there is no evidence that one NSAID is more effective than another.⁴
Choice of agent may depend on side effect profile.
Indomethacin may be more likely to cause CNS adverse effects.⁵
Naproxen is suggested as having the lowest cardiovascular risk (see special considerations, ischemic heart disease (page 12).⁶
Nonselective NSAIDs are less expensive, are readily available, and are as effective and at least as safe as selective agents.⁴
o Oral corticosteroids
Useful if patient cannot take colchicine or NSAID or if the attack would not resolve otherwise.
Generally there is no need to taper unless patient has a history of frequent flares.⁴
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o Intra-articular corticosteroids
Useful for patients who cannot take oral medication and who have one or two acutely inflamed joints.
Requires technical skill and not all physicians may be comfortable carrying out the procedure.
Important to exclude infection by joint aspiration and analysis even in patients with a history of several gout attacks.
Suggestion is triamcinolone acetonide⁴
Small joint (finger, toe) 10 mg
Medium joint (wrist, ankle, elbow) 30 mg
Large joint (knee) 40 mg
Some guidelines express a preference for one therapy over another; other guidelines indicate all are appropriate. Choice of drug may depend on age and comorbidities such as
o Renal function
o Cardiovascular disease including heart failure
o Gastroesophageal disease
o Concurrent medications
o Drug allergy
See Question 3, Special Considerations page 12 for further details.
Treatment choice may depend on whether the patient is already on prophylactic colchicine. If so, and the patient has received acute colchicine therapy in the last 14 days, choose an NSAID or oral corticosteroid.2
Treatment should continue until symptoms resolve, approximately 7 days. Generally acute gout attacks resolve spontaneously although resolution is faster with treatment.
A summary of treatment options is in Table 2.
Question 2. How should urate lowering therapy (ULT) be started and monitored?
Starting therapy
Guidelines⁷⁻⁹ recommend initiating ULT in patients with gout and any one of:
o 2 or more attacks of acute gouty arthritis in one year
o Tophus or tophi by clinical exam or imaging study
o Chronic kidney disease stage 2 or greater
o Past urolithiasis
o Need to continue therapy with diuretics
Different guidelines offer various options for the initiation of ULT.
o The American Guidelines suggest that therapy can be initiated during an acute attack of gout provided that effective anti-inflammatory or colchicine treatment has been started.⁷
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o This recommendation is based on the results of a recently published single site RCT that evaluated starting allopurinol during an acute attack versus starting on day 11 after the attack started. Results reported
No difference in pain scores on any of days 1 to 10
No difference in the number of gout flares during days 1 to 30
All flares were at least 5 days removed from the initiation of allopurinol and none involved exacerbation of the index joint.¹⁰
o Other guidelines⁸ suggest waiting 1-2 weeks after resolution of the acute attack as therapy may precipitate further attacks.
o Our content expert supports initiating allopurinol during the acute attack to achieve better compliance and long-term outcomes. Therapy should start with a low dose (50 to 100 mg daily).
Therapy should be life-long and should not be stopped during an acute attack.
Monitoring therapy
The therapeutic goal of ULT is to prevent acute flares, prevent the development of tophi, help dissolve existing tophi, and prevent the development of chronic gouty arthropathy.⁹
During an acute attack, serum urate levels may fall. NICE suggests measuring urate 4 to 6 weeks after an acute attack of gout to confirm hyperuricemia.⁸
Guidelines recommend that therapy should be titrated to maintain an SUA level of < 360 µmol/L, well below the saturation point for monosodium urate of 405 µmol/L.
o The benefits associated with reaching a target SUA of < 360 µmol/L have been confirmed by retrospective observational analyses.¹¹⁻¹⁴
o A post hoc analysis of an RCT15 comparing febuxostat to allopurinol reported flare rates in patients with SUA levels < 360 vs ≥ 360 µmol/L.
During the initial weeks of the trial, flare rates were comparable between the two groups.
By the last 4 weeks of the 52 week trial, the mean rate of flares among patients with a mean post baseline SUA < 360 µmol/L was significantly lower than that among patients with a mean post-baseline SUA ≥ 360 µmol/L .
6% vs 14% respectively; P <0.05
Patients in the trial received prophylaxis for the initial 8 weeks only.
o Although 360 µmol/L was used as the target point in most studies, another study suggests that benefit may be seen at SUA levels of < 400 µmol/L.¹³ In some patients, a target of < 300 µmol/L is required to improve signs and symptoms (e.g., patients with tophaceous gout).⁷
Monitoring serum urate levels: two approaches have been suggested:
o OPTION 1: During dose titration of urate lowering therapy, check serum urate levels regularly (every 2-5 weeks). Once the target has been reached, check urate levels every 6 months.⁷
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o OPTION 2: Determine the level within 2 to 4 weeks of a dose adjustment, with confirmation 3 months later. Once goal values are confirmed, measure levels every 6 months for the next year and then annually unless medications or lifestyle factors that might alter urate levels have been introduced in the interim.¹⁶
Rate of lowering:
o It is suggested to lower the serum uric acid slowly (no more than 60 to 120 µmol/L per month) to minimize the occurrence of gout flares. These occur more frequently in the early months of urate lowering treatment and might influence compliance.¹⁶
Pharmacologic Choices
Xanthine oxidase inhibitors (allopurinol and febuxostat)
Allopurinol and febuxostat both inhibit production of uric acid.
Most guidelines recommend allopurinol as first-line therapy.
They have different chemical structures and febuxostat may be an option for patients who have a hypersensitivity to or are otherwise intolerant of allopurinol.
According to the guidelines from ACR which do not consider cost, both are considered first-line options.⁷
Allopurinol and febuxostat should not be used in combination.
A recent Cochrane Review reported that after 3 years, there were no statistically significant differences regarding effectiveness and harms between febuxostat 80 mg or 120 mg and allopurinol groups.¹⁷
The urate lowering efficacy of febuxostat compared to allopurinol has been studied in 3 RCTs.¹⁵,¹⁸,¹⁹
o All 3 reported febuxostat, in doses of 80 mg or above, to be more effective than fixed-dose allopurinol (300 mg) in achieving a serum urate concentration of less than 360 µmol/L.
o In the 2 studies that reported number of gout flares, there was no difference between febuxostat and allopurinol.
o Authors comment that allopurinol might have been more effective at lowering urate levels if the dose had been titrated upwards as is recommended.
o None of the RCTs included patients with CrCl <30 ml/min and none reported the mean SUA achieved in the febuxostat and allopurinol groups.
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How to prescribe allopurinol
Starting dose
o Usual starting dose is 100 mg once a day (preferably taken with food).
o Guidelines suggest starting at 50 mg/day in patients with
Stage 4 or 5 chronic kidney disease;⁷ NICE suggests Stage 3⁸
Frequent attacks
Hepatic impairment, and
In the elderly.⁸
o An alternative approach for patients with renal insufficiency to minimize the risk of allopurinol hypersensitivity syndrome is a starting dose of 1.5 mg per ml/min of eGFR.20
A suggested regimen20 for starting allopurinol at different levels of eGFR is
Stage of Kidney Function eGFR Starting dose
Stage 5 <5 50 mg/week
Stage 5 5-14 50 mg twice weekly
Stage 4 15-29 50 mg every 2 days
Stage 3B 30-44 50 mg/day
Stage 3A 45-59 50 mg/100 mg on alternate days
Stage 2 60-89 100 mg/day
Stage 1 (normal) 90-130 150 mg/day
Stage 1 (normal) >130 200 mg/day
Dose increments should be no more than 50 mg daily every 4 weeks to the minimum daily dose necessary to achieve the SUA target level.16
Titrating to target and maximum dose
o Gradually increase dose every 2-4 weeks by 100 mg (50 mg if initial dose is 50 mg) to achieve SUA target.
o Dose range is 100 mg to 800 mg daily; commonly 300 mg daily.5
Doses over 300 mg should be taken in divided doses to help minimize any gastrointestinal adverse effects. 8
o Dose can be raised above 300 mg daily, even in patients with renal impairment, provided that it is accompanied be adequate patient education and monitoring for drug toxicity ( e.g. pruritus, rash, elevated hepatic transaminases).7
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Allopurinol Hypersensitivity Syndrome (AHS)
This life-threatening toxicity syndrome is characterized by vasculitis, rash, eosinophilia, hepatitis, and progressive renal failure.21
Onset of symptoms frequently occurs after 2 to 8 weeks of starting allopurinol.22
Mortality rates of 15% to 37.5% have been reported.21
The syndrome probably involves an interaction of metabolite accumulation and a drug specific immune response.24
Predisposing factors include: advanced age, Southeast Asian/Chinese ethnicity, renal impairment, and high allopurinol initiation dosages.25
Our content expert stressed the importance of informing patients to report if they experience any NEW pruritus or skin rash as this represents allopurinol intolerance and might be an initial indicator of allopurinol hypersensitivity syndrome.
Following current recommendations, especially starting with low dose and increasing slowly, the risk of AHS is lower than previously thought.
A recently published retrospective case-control study concluded that starting allopurinol at a dose of 1.5 mg per unit of eGFR may be associated with a reduced risk of AHS. 20
Before starting allopurinol, consider HLA-B*5801 in selected patients, specifically in subpopulations at higher risk for severe allopurinol hypersensitivity reactions (e.g. Koreans with stage 3 or worse CKD, and Han Chinese and Thai irrespective of renal function).7 If the test is positive in these subpopulations, do not prescribe allopurinol.
Febuxostat
o In Canada, febuxostat is available only as an 80 mg tablet and this is the usual recommended dose.
o According to the official monograph26 no dosage adjustment is needed in
Elderly patients
Patients with mild to moderate hepatic impairment (Child-Pugh Class A or B)
Patients with mild or moderate renal impairment (CrCl 30-89 ml/min)
Uricosuric agents
Probenecid is the commonly referred to uricosuric agent for urate lowering.
o Tablets are no longer being manufactured for the Canadian market but capsules may be available from some compounding pharmacies.
Uricosuric agents are not recommended in patients with
o eGFR below 50 ml/min
o A history of urolithiasis
Patients should increase fluid intake.²⁷
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Uricases
Pegloticase, a recombinant pegylated uricase, is an expensive biologic therapy approach for gout.
o It is appropriate for patients with severe gout disease burden and refractoriness to, or intolerance of, appropriately dosed oral ULT options.7
It is currently not available in Canada.
Prophylaxis while starting ULT
Initiation of any urate lowering therapy may precipitate acute gouty flares because of the sudden decrease in SUA levels.2
To minimize the risk of flares, prophylactic therapy is recommended.16
Low doses of colchicine or NSAIDs may be used for prophylactic therapy.(See Table 2)
o For patients who cannot tolerate either of these therapies, low dose oral prednisone (≤ 10 mg daily) may be used.2 This is a consensus recommendation with little evidence of the benefit of this low dose and the known risks of prolonged corticosteroid use.
Duration of prophylactic therapy during the initiation of ULT:
o The ACR guidelines 2 recommend continuing prophylaxis if there is any clinical evidence of continuing gout disease activity and/or the target SUA has not yet been achieved.
Continue prophylaxis for the greater of:
6 months’ duration15, 19, 28
3 months after achieving the target SUA level appropriate for the patient without tophi detected on physical examination
6 months after achieving the target SUA level appropriate for the patient where there has been resolution of tophi previously detected on physical examination.
o Because of potential toxicity, the continued use of colchicine or NSAIDs beyond these recommended durations is not recommended.16
o Our content expert suggests:
Colchicine is the drug of first choice for prophylaxis.
A dose of 0.6 mg daily is effective for most patients.
Dose range is usually 0.6 to 1.2 mg daily and 1.8 mg is the high maximum. Regimens greater than 0.6 mg daily should be given in divided doses.
Patients with very high SUA levels may be started on 1.2 mg daily and can be decreased to 0.6 mg daily if no attacks occur after a few months, or if diarrhea occurs.
Duration of prophylaxis:
At least 3 months after last attack, provided normouricemia is attained.
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Question 3. What are some special considerations when treating gout?
Elderly patients may have comorbidities or be taking other medications that limit the use of NSAIDS or colchicine; oral corticosteroids may be appropriate.4
End stage renal disease and renal transplantation: Colchicine is not removed by dialysis and NSAIDs may further decrease renal function and may be associated with a high risk of upper GI bleeding in dialysis patients. Oral corticosteroids may be appropriate.4
Renal impairment and NSAIDS
o The following is the recommendation from our local nephrologist
Caution against the use of any NSAID in all patients with chronic kidney disease
eGFR <60 ml/min, or
a higher GFR (stage I and II CKD) with significant proteinuria
These drugs all accumulate in patients with advanced CKD stages 4 and 5 (eGFR<30) and one would thus expect greater risk of adverse effects including GI bleeding.
NSAIDS cause reduced renal blood flow, acute functional renal failure, hyporeninemic hypoaldosteronism with hyperkalemia, edema and hypertension as well as hematuria, papillary necrosis, nephrotic syndrome with minimal change disease, proliferative glomerulonephritis acute interstitial nephritis, and acute tubular necrosis. Whether NSAIDs can cause chronic interstitial nephritis is unclear although this remains likely. As well, NSAIDs will antagonize all antihypertensive drugs and make hypertension worse.
For patients with acute gout and CKD, colchicine rather than any NSAID is recommended. Prednisone would be the next drug to use after colchicine. If a NSAID has to be used then sulindac may have a lower renal risk as it does not decrease urinary prostaglandin levels to the same extent as other NSAIDs.
History of ischemic heart disease or heart failure:
o Short term or long term use of NSAIDs can exacerbate heart failure.
o Long term use of NSAIDs has been associated with increased risk of MI. Naproxen appears to be least likely to show this association.6
o A large nationwide cohort study found that even short-term use of most NSAIDs was associated with increased risk of death and recurrent MI in patients with prior MI.
When analyzed by the individual NSAID, only diclofenac was associated with an increased risk when taken for periods of 7 days of less (hazard ratio, 3.26; 95% confidence interval, 2.57 to 3.86 for death/MI at day 1 to 7 of treatment).
Use of naproxen was not associated with a significantly increased risk of death or MI for treatments up to 90 days in duration, but point estimates suggested increased risk and confidence intervals were large.
The study concluded that neither short- nor long-term treatment with NSAIDs is advisable in a population with a history of prior MI.29
Concomitant anticoagulation: Avoid NSAIDs in patients on anticoagulation and prescribe low-dose colchicine or oral corticosteroids.4
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Concomitant diuretics: Diuretics increase urate levels by decreasing urate excretion in a dose-dependent relationship.30 Use of thiazides and loop diuretics is significantly associated with the development of gout; this association has not been shown for potassium-sparing agents such as triamterene and spironolactone.31
o Asymptomatic diuretic-induced hyperuricemia is not an indication for discontinuing the diuretic or adding urate lowering therapy.
o For diuretic-induced gout, the approach may vary according to the indication for the diuretic:
Edema and HF: It may not be advisable to stop the diuretic and higher doses of allopurinol may be needed to achieve urate target levels.32
Hypertension: ACE inhibitors and angiotensin receptor blockers (ARBs) may attenuate the rise in urate from diuretics and augment their antihypertensive effect so a lower dose of diuretic may be required for control of hypertension. Losartan, in particular appears to have uricosuric activity.33-35 Replacing the diuretic-induced fluid loss will also mitigate the rise in urate.
o Most patients with diuretic-induced gout are treated with ULT such as allopurinol.32
Our content expert suggests substituting the diuretic with losartan, if that is an option in a particular situation.
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Question 4. What is the role of lifestyle in prevention of gout?
Recommendations for advising patients about lifestyle have changed somewhat.
Gout is associated with cardiovascular disease, hypertension, abdominal obesity, hyperlipidemia, and diabetes. Lifestyle recommendations for prevention of gout should not contradict recommendations that would benefit those associated conditions.
Evidence for the benefit of lifestyle changes comes from observational studies rather than randomized controlled trials.7 Therefore the findings represent associations of lifestyle factors with gout and not necessarily a causal link between those factors and gout.
Whereas previously there were recommendations to limit intake of high purine fruit and vegetables, this is no longer the case since intake of fruits and vegetables will benefit the other conditions associated with gout.
The US Guideline7 makes general recommendations and specific recommendations to avoid, limit, or encourage intake of various foods.
o General recommendations include:
Weight loss for obese patients, to achieve normal BMI
Exercise
Smoking cessation
Healthy overall diet
Stay well hydrated
o Specific dietary recommendations include
Avoiding organ meats high in purine content and high fructose corn syrup sweetened beverages or foods
Limiting red meats, seafood with high purine content (e.g., sardines, shellfish), naturally sweet fruit juices, sweetened food products and sodium rich foods
Alcohol overuse should be avoided (defined as more than 2 servings a day for men and 1 serving a day for women). This applies specifically to beer and spirits, but amounts of wine should also be limited.
Low or non-fat dairy products are encouraged.
In addition, drinking at least 3 to 4 or more cups of coffee (including decaffeinated) has been associated with a decreased incidence of gout.36
While adherence to lifestyle recommendations will help prevent gout flares, most patients will require drug therapy for optimal results.7
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References
1. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) - CPhA Monograph ¬ in¬ e-CPS, electronic Compendium of Pharmaceuticals and Specialties. Ottawa, ON: Canadian Pharmaceutical Association; 2013.
2. Khanna D, Khanna PP, Fitzgerald JD, Singh MK, Bae S, Neogi T, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis care & research. 2012;64(10):1447-61.
3. Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis and Rheumatism. 2010;62(4):1060-8.
4. Becker MA. Treatment of Acute Gout. Up To Date [Internet]. 2013.
5. Laubscher T, Dumont Z, Regier L, Jensen B. Taking the stress out of managing gout. Canadian Family Physician Medecin de Famille Canadien. 2009;55(12):1209-12.
6. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Medicine. 2011;8(9):e1001098.
7. Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care & Research. 2012;64(10):1431-46.
8. Gout 2012 November 20 2013. Available from: http://cks.nice.org.uk/gout - topic summary.
9. Hamburger M, Baraf HS, Adamson TC, 3rd, Basile J, Bass L, Cole B, et al. 2011 recommendations for the diagnosis and management of gout and hyperuricemia. The Physician and Sportsmedicine. 2011;39(4):98-123.
10. Taylor TH, Mecchella JN, Larson RJ, Kerin KD, Mackenzie TA. Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial. The American Journal of Medicine. 2012;125(11):1126-34.e7.
11. Wu EQ, Patel PA, Mody RR, Yu AP, Cahill KE, Tang J, et al. Frequency, risk, and cost of gout-related episodes among the elderly: does serum uric acid level matter? The Journal of Rheumatology. 2009;36(5):1032-40.
12. Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis and Rheumatism. 2004;51(3):321-5.
13. Yamanaka H, Togashi R, Hakoda M, Terai C, Kashiwazaki S, Dan T, et al. Optimal range of serum urate concentrations to minimize risk of gouty attacks during anti-hyperuricemic treatment. Advances in Experimental Medicine and Biology. 1998;431:13-8.
14. Sarawate CA, Patel PA, Schumacher HR, Yang W, Brewer KK, Bakst AW. Serum urate levels and gout flares: analysis from managed care data. Journal of Clinical Rheumatology: practical reports on rheumatic & musculoskeletal diseases. 2006;12(2):61-5.
15. Becker MA, Schumacher HR, Jr., Wortmann RL, MacDonald PA, Eustace D, Palo WA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. The New England Journal of Medicine. 2005;353(23):2450-61.
16. Becker MA. Prevention of Recurrent Gout Up To Date [Internet]. 2013.
17. Tayar JH, Lopez-Olivo MA, Suarez-Almazor ME. Febuxostat for treating chronic gout. The Cochrane Database of Systematic Reviews. 2012;11:Cd008653.
18. Schumacher HR, Jr., Becker MA, Wortmann RL, Macdonald PA, Hunt B, Streit J, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis and Rheumatism. 2008;59(11):1540-8.
19. Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Research & Therapy. 2010;12(2):R63.
20. Stamp LK, Taylor WJ, Jones PB, Dockerty JL, Drake J, Frampton C, et al. Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol. Arthritis and Rheumatism. 2012;64(8):2529-36.
21. Singer JZ WS. The Allopurinol Hypersensitivity Syndrome. Arthritis & Rheumatism. 1986;29:6.
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22. Final Recommendation Febuxostat. Common Drug Review [Internet]. 2011. Available from: http://www.cadth.ca.
23. Lang PG, Jr. Severe hypersensitivity reactions to allopurinol. Southern Medical Journal. 1979;72(11):1361-8.
24. Arellano F, Sacristan JA. Allopurinol hypersensitivity syndrome: a review. The Annals of Pharmacotherapy. 1993;27(3):337-43.
25. Lee HY, Ariyasinghe JT, Thirumoorthy T. Allopurinol hypersensitivity syndrome: a preventable severe cutaneous adverse reaction? Singapore Medical Journal. 2008;49(5):384-7.
26. Product monograph: Uloric (febuxostat 80 mg tablets) 2010.
27. Kapur S, Kraag G. Musculoskeletal Disorders: Gout and Hyperuricemia. Therapeutic Choices. electronic. Ottawa, ON: Canadian Pharmacists Association; 2013.
28. Wortmann RL, Macdonald PA, Hunt B, Jackson RL. Effect of prophylaxis on gout flares after the initiation of urate-lowering therapy: analysis of data from three phase III trials. Clinical Therapeutics. 2010;32(14):2386-97.
29. Schjerning Olsen AM, Fosbol EL, Lindhardsen J, Folke F, Charlot M, Selmer C, et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation. 2011;123(20):2226-35.
30. Reyes AJ. Cardiovascular drugs and serum uric acid. Cardiovascular Drugs and Therapy. 2003;17:17.
31. Bruderer SJS, Bodmer M, Meier CR. Use of diuretics and risk of incident gout: Population-based case-control study. Arthritis & Rheumatism. 2013.
32. Becker MA. Diuretic-induced hyperuricemia and gout Up To Date [Internet]. 2013.
33. Tikkanen I, Omvik P, Jensen HA. Comparison of the angiotensin II antagonist losartan with the angiotensin converting enzyme inhibitor enalapril in patients with essential hypertension. Journal of Hypertension. 1995;13(11):1343-51.
34. Manolis AJ, Grossman E, Jelakovic B, Jacovides A, Bernhardi DC, Cabrera WJ, et al. Effects of losartan and candesartan monotherapy and losartan/hydrochlorothiazide combination therapy in patients with mild to moderate hypertension. Losartan Trial Investigators. Clinical Therapeutics. 2000;22(10):1186-203.
35. Wurzner G, Gerster JC, Chiolero A, Maillard M, Fallab-Stubi CL, Brunner HR, et al. Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout. Journal of Hypertension. 2001;19(10):1855-60.
36. Singh JA, Reddy SG, Kundukulam J. Risk factors for gout and prevention: a systematic review of the literature. Current Opinion in Rheumatology. 2011;23(2):192-202.
37. Highlights of prescribing information COLCRYS (colchicine, USP tablets)2009 November 20 2013. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022351lbl.pdf.
38. Micromedex 2.0 Drug Information Database. Ann Arbor, Michigan: Truven Health Analytics Inc; 2013.
17
Table 2 Summary of oral drug treatments for acute and prophylactic treatment of gout
Drug/Class
Dose Adverse Effects Renal/hepatic considerations Comment Cost for
7 & 30 daysa
Colchicine
ACUTE
1.2 mg stat then 0.6 mg 1
hour later for total 1.8 mg
on the first day
0.6 mg once or twice daily
PROPHYLAXIS FOR ULT
0.6 mg once or twice daily
for 6 to 12 months
Abdominal pain and
cramps, diarrhea,
nausea, vomiting
For acute flare:
If CrCl <30 ml/min do not repeat
treatment course more often than once
every two weeks.37
For patients on dialysis total
recommended dose for acute flare is
0.6 mg. 37
No dose adjustment necessary for
hepatic impairment but with severe
impairment do not repeat treatment
course more than once every 2 wks 37
For prophylaxis:
CrCl <30 mL/min: start at 0.3mg daily &
monitor closely if dose increases are
required. Patients on dialysis, 0.3 mg
twice weekly; monitor closely
Consider dosage reduction in severe
hepatic impairment.38
Not recommended for acute treatment if
cannot be given < 36 hours after onset2
Concomitant use with P-gp and
cytochrome P450 inhibitors can lead to
colchicine toxicity (e.g., erythromycin,
clarithromycin, verapamil, azole
antifungals, anti-virals, cyclosporine
Lipid-lowering agents (statins and
fibrates) increase the risk of
rhabdomyolysis)
CHECK WITH PHARMACIST or DRUG
INTERACTION REFERENCE FOR
PATIENT-SPECIFIC INTERACTIONS
$ 3.85/ 7 days
$ 7.70 – 15.40/ 30
days
Naproxen
NSAID
ACUTE
750 mg stat then 500 mg
BID
PROPHYLAXIS FOR ULT
250 MG BID
GI upset, fluid retention,
hypertension, renal
impairment.
Contraindicated with
- CrCl <30 ml/min 1,38
- CVD especially heart failure and
hard to control hypertension
- Coagulopathy or anticoagulant
therapy
Caution advised if CrCL < 60mL/min)
May need gastroprotection depending
on risk. Contraindicated with active
gastroduodenal ulcer
All NSAIDs carry black box warnings
concerning serious cardiovascular
thrombotic events which can be fatal,
and risk of serious gastrointestinal
adverse events especially in the elderly.
Naproxen appears to have lowest CV
risk of any NSAID.
No evidence that indomethacin is more
$2.95/ 7 days
(500 mg bid)
$6.41/ 30 days
(250 mg bid)
Indomethacin
NSAID
ACUTE
50 mg TID
GI upset, fluid retention,
hypertension, renal
Caution advised38 if CrCl < 60mL/min)
Liver disease: Child-Pugh Class III,
$ 9.37/ 7 days
(50 mg tid)
18
a wholesale costs from McKesson Pharmaclik online as of Nov 15, 2013 and do not include prescribing fee
PROPHYLAXIS FOR ULT
No mention of use of
indomethacin for
prophylaxis in any reference
consulted, although not
specifically contraindicated
for this
impairment.
Neurological:
Headache, dizziness,
somnolence 38
initiate with lowest recommended
dosage, monitor patient closely and
reduce dosage if necessary
Elderly: initiate with the lowest
recommended dosage, monitor patient
closely
effective than other NSAIDs.
Indomethacin more likely to cause
neurological adverse effects 10%
Prednisone
Corticosteroid
ACUTE
0.5 mg/kg/day for 5 to 7
days 2
PROPHYLAXIS FOR ULT
≤ 5 – 10 mg/day
Usually reserved for people
with end-stage renal
disease or those who
cannot take NSAIDs or
colchicine
Hypertension, edema,
impaired glucose
tolerance, increased
appetite, osteoporosis,
disturbance in mood 38
Renal insufficiency: no adjustment
necessary
Not removed by hemodialysis 38
No information on dosing in hepatic
insufficiency, except a precaution that
corticosteroid effect may be increased
in cirrhosis, due to decreased
metabolism. 38
Does not need to be tapered when
given for acute treatment.
Prophylactic use is not well supported
by evidence and is almost certain to
cause adverse effects.
$1.96/ 7 days
(70 Kg patient,
35 mg/day)
Urate Lowering Therapy
Allopurinol
Xanthine
oxidase
inhibitor
Start 50 or 100 mg/day
Increase by 50 or 100
mg/day q 2 – 4 weeks to
maximum of 800 mg
Skin rash, GI upset,
hepatotoxicity, fever,
hypersensitivity
syndrome, xanthine
stones
Start 1.5 mg/mL/min eGFR
Increase by 50 mg q 2-4 weeks 16, 20
Starting dose of 50 mg/day is
recommended in the elderly and
patients with hepatic impairment or
frequent attacks.8
$ 6.38/ 30 days
(300 mg/d)
$15.60/ 30 days
(800 mg/d)
Febuxostat
Xanthine
oxidase
inhibitor
80 mg daily
Nausea, arthralgia, skin
rash (at higher dose),
increased hepatic
aminotransferase
levels.
Mild to moderate renal impairment:
(CrCl, 30-89 mL/min), no dosage
adjustment necessary.
Mild to moderate hepatic impairment:
(Child-Pugh class A or B), no dosage
adjustment necessary. 38
NS Pharmacare covers febuxostat only
in patients who have documented
hypersensitivity to allopurinol
$ 51.76/ 30 days
(80 mg/day)
19
Appendix 1 Table of select gout studies
Author
Year
N
Length
Population Comparators Outcome Results
Comments/Implications
High vs low dose colchicine for acute treatment of gout
Terkeltaub 3
2010
185
32 hrs
At least 2 gout flares
previous 12 mos
95% male
Mean age 51
High dose:
colchicine 1.2 mg
followed by 0.6 mg
hourly for 6 hrs
(4.8 mg total)
Low dose
colchicine 1.2 mg
followed by 0.6 mg
(1.8 mg total)
Placebo
≥ 50 reduction in
pain intensity
Serious adverse
events
Pain relief
No sig diff b/w high and low
dose colchicine in pain relief.
NNT for both doses vs placebo =
5
Adverse events
High dose: 77% had AE all of
which included diarrhea. 19 %
had serious AE.
Low dose: 37% had AE 23% of
which had diarrhea. None had
serious AE.
NNH for high dose vs low dose
or placebo ~ 2.
Colchicine had to be given within 12 hours
which may not always be possible.
Industry funded trial with one author
holding 2 patents pertaining to dosing of
colchicine with clarithromycin.
Low dose colchicine is as effective as high
dose colchicine with far fewer AEs.
Starting allopurinol during an acute gout flare
Taylor 10
2012
57
30 days
Presenting within 7
days of acute gout
attack
100% male
Mean age ~60
Allopurinol 300mg
daily
Placebo
Both given for 10
days starting within
7 days of onset of
acute attack
All patients given
allopurinol 300 mg
daily on days 11-30
Pain score on
day 1 to 10
Gout flares day 1
to 30
Pain score
No sig diff. Went from ~6.5/10
to ~0.23 at day 10
Duration of incident attack
No sig diff. ~ 4 days in each
group
Gout flares day 1 to 30
2 in allopurinol group
3 in placebo group
Limitation is that this is a small, single-
centred study with all male subjects.
All patients received indomethacin 50 mg
TID for 10 days and colchicine 0.6 mg BID
for 90 days.
In uncomplicated gout NSAID,
prophylactic colchicine 0.6 mg BID, and
allopurinol may be started during an acute
attack.
20
Author
Year
N
Length
Population Comparators Outcome Results
Comments/Implications
Allopurinol vs Febuxostat
Schumacher18
2008
1072
28 weeks
Diagnosis of gout
Serum urate >480
94% male
Mean age 52
Creatinine <177
Creatinine >133 =
4%
Febuxostat 80 mg
Febuxostat 120 mg
Febuxostat 240 mg
Allopurinol 100 mg if
creatinine >133 or
300 mg if creatinine
<133
Placebo
Proportion of
subjects with
urate <360
Adverse events
Proportion of subjects with
urate <360 at 28 weeks:
- Febuxostat 80 mg 76%
- Febuxostat 120 mg 87%
- Febuxostat 240 mg 94%
- Allopurinol 41%
- Placebo 1%
8 weeks of prophylaxis provided with
naproxen 250 mg BID or colchicine 0.6 mg
QD
Not enough subjects with renal impairment
to be able to definitively determine efficacy
or harms.
Febuxostat 240 was included for safety
rather than efficacy analysis. Generally
there was no clinically significant
difference in AEs among the groups,
although febuxostat 240 mg had higher
rates of joint-related symptoms (13% vs
7%), diarrhea (13% vs 6%) and dizziness
(7% vs 2%) than allopurinol.
Mean levels of urate acid achieved in each
group were not reported.
Febuxostat led to more subjects achieving
target urate level but allopurinol was given
at fixed doses and not titrated.
Becker 15
2005
762
52 weeks
Diagnosis of gout
Serum urate >480
96% male
Mean age 52
Mean urate ~585
Creatinine <133 or
CrCl > 50 ml/min
Febuxostat 80 mg
Febuxostat 120 mg
Allopurinol 300 mg
Proportion of
subjects with
urate <360
Acute flares
Adverse events
Proportion of subjects with
urate <360 at last 3 monthly
visits:
- Febuxostat 80 mg 53%
- Febuxostat 120 mg 62%
- Allopurinol 300 mg 21%
Gout flares
- Febuxostat 80 mg 22%
- Febuxostat 120 mg 36%
- Allopurinol 300 mg 21%
More patients achieved urate target level
but there was no difference in number of
flares between febuxostat 80 mg and
allopurinol 300 mg.
Allopurinol was given at fixed dose and not
titrated as you would expect over a one
year period.
21
Author
Year
N
Length
Population Comparators Outcome Results
Comments/Implications
Adverse events
No difference between groups
Becker 19
2010
2269
6 months
Diagnosis of gout
Serum urate >480
94% male
Mean age 53
Mean urate ~576
CrCl 30-59 ml/min =
18%
Febuxostat 40 mg
Febuxostat 80 mg
Allopurinol 200 mg if
CrCl < 60 ml/min or
300 mg if CrCl ≥ 60
ml/min
Proportion of
subjects with
urate <360
Adverse events
Proportion of subjects with
urate <360 at last visit:
- Febuxostat 40 mg 45%
- Febuxostat 80 mg 67%
- Allopurinol 2-300mg 42%
Results were similar in patients
with renal impairment
Adverse events
No difference between groups
Febuxostat 40 mg was non-inferior to
allopurinol in all outcomes.
Febuxostat 80 mg was more effective in
lowering urate to target levels than
allopurinol but not more effective in
reducing flares.
Low starting dose to decrease risk of allopurinol hypersensitivity syndrome (AHS)
Stamp 20
2012
211 Gout cases with and
without AHS
Doses of allopurinol
in relation to eGFR
Development of
AHS
90% of AHS cases occurred
within first 180 days
Mean starting dose of
allopurinol for
- controls = 112 mg/d
- cases = 184 mg/d
Increase in AHS as starting
dose of allopurinol increased
Case-control study, not RCT.
Analysis indicated a reasonable practical
starting dose of allopurinol to minimize
risks of AHS is 1.5 mg/ml/min eGFR.
